CN102740893B - Dry-coated orally disintegrating tablet - Google Patents

Abstract

Disclosed is a dry-coated orally disintegrating tablet which is a dry-coated molded product characterized in that an inner core comprises powder particles having low moldability, and which has excellent disintegrating properties and proper hardness as a whole. Specifically disclosed is a dry-coated orally disintegrating tablet comprising an inner core and an outer layer that covers the periphery of the inner core, wherein the ratio of the thickness of the inner core to the whole thickness of the tablet is 30 to 80% and the outer layer comprises (a) crystalline cellulose, (b) a sugar or a sugar alcohol, and (c) at least one specific component selected from the group consisting of crospovidone, a starch, hydroxypropyl cellulose having a low substitution degree and carmellose.

Description

Compression-coated orally disintegrating tablets

technical field

The present invention relates to compression-coated orally-disintegrating tablets. In particular, the present invention relates to a press-coated formulation comprising an inner core comprising a powder/granular material having poor formability and an outer layer surrounding the inner core, as a final formulation (hereinafter also referred to as "compressed Coated orally disintegrating tablet") exhibits suitable hardness and excellent disintegration in the oral cavity. Specifically, the present invention relates to a compression-coated orally disintegrating tablet in which even when the tablet is taken with a small amount of water or without water, the outer layer is rapidly disintegrated, and then the granules or powder in the inner core are dispersed in the oral cavity .

Background technique

Due to the aging society, many attempts have been made to develop orally disintegrating tablets that can be easily taken by elderly people who have difficulty or impairment in swallowing tablets. Therefore, there is an increasing need to develop orally disintegrating tablets containing various active ingredients. In the case where the active ingredient has a bitter taste, it may be necessary to mask the bitter taste in order to formulate it into an orally disintegrating tablet or the like. Likewise, controlled release of the active ingredient may be necessary to increase the bioavailability of the active ingredient. However, many of these functional particles tend to have some adverse effects on tablet formability (for example, they lack sufficient hardness when uniformly distributed in the tablet), so a large amount of additives such as excipients and The binder avoids adverse effects which inevitably lead to tablets having inconveniently large dimensions.

Patent Reference 1 discloses a compression-coated rapidly disintegrating tablet in a unique form not previously well known. Press-coated tablets have a bilayer structure consisting of an inner core and an outer layer, and they have attracted attention as a new technology for tablet formulation. However, the design of the press-coated formulation disclosed in Patent Reference 1 focuses on the solubility and degradability of the inner core, and the ingredients of both the inner core and the outer layer include ingredients having formability (for example, as in which only As indicated in the results of Example 2 where the composition of the inner core was compressed into a tablet, it seems that the composition of the inner core in Patent Reference 1 has formability and a certain hardness). Therefore, Patent Reference 1 does not attempt to apply a powder/granular material having poor formability to core components, and the document only discloses a limited range of components that can be used for the core. Furthermore, Patent Reference 1 discloses a combination of "microcrystalline cellulose" and "sugar or sugar alcohol" as an ingredient of the outer layer of a press-coated tablet, but it fails to disclose further inclusion of the "specific ingredient" of the present invention The combination.

Moreover, the specific ingredients of the present invention (such as carmellose, low-substituted hydroxypropyl cellulose, native starch, and/or polyvinylpolypyrrolidone (crospovidone)) that are essential for the outer layer are described in the patent Dissolved/disintegrated accelerators disclosed in reference 1 as inner cores (see page 9, lines 17-26). Specifically, Patent Reference 1 explains that the outer layer contains ingredients with good formability, and preferably it further contains ingredients with good solubility and/or disintegration; while the inner core also contains ingredients with good solubility. and/or disintegratable ingredients, and it may further comprise a dissolution/disintegration accelerator (see page 8, lines 14-17). Furthermore, Patent Reference 1 shows that the inner core and outer layer are used to prepare a molded product having a two-layer structure in which only the outer layer requiring hardness has good formability, while the inner core has excellent solubility/ disintegratability; and its inventors have thus achieved a molded product with fast dissolution/disintegration time and sufficient formability (see page 5 lines 5-11 and abstract). In other words, it seems that the molded product in Patent Reference 1 exhibits its characteristics by containing ingredients such as dissolution/disintegration accelerators only in the inner core (ie excluding them from the outer layer). On the contrary, the specific components in the present invention are essential components for the outer layer and thus are used in the opposite manner to the components in the invention of Patent Reference 1.

Patent Reference 2 discloses some tests using microcapsule-like particles in the composition of the core of the formulation in Patent Reference 1 as described above. Specifically, Patent Reference 2 discloses some studies on the application of microcapsule-like granules to the inner cores of press-coated tablets, and some successful examples of press-coated formulations containing microcapsule-like granules in their inner cores. , prepared according to the given method using an outer layer comprising lactose and microcrystalline cellulose. Patent Reference 2 discloses the invention of press-coated tablets containing microcapsule-like granules in their inner cores, but fails to disclose or suggest research on the application of press-coated tablets to orally disintegrating tablets. In addition, in Patent Reference 2, other than lactose and microcrystalline cellulose, there is no study on the applicable ingredients for the outer layer of a press-coated formulation containing microcapsule-like particles in its inner core. Of course, Patent Reference 2 does not disclose the combination of essential ingredients for the outer layer of the present invention. Also, Patent Reference 2 fails to disclose mannitol as an ingredient of the outer layer of a press-coated formulation.

Patent Reference 3 relates to an orally disintegrating tablet containing mannitol, but does not clearly disclose a press-coated formulation.

[Patent Reference 1] WO 2003/028706 A1

[Patent Reference 2] WO 2005/097041 A1

[Patent Reference 3] JP 2001-058944 A.

Contents of the invention

(technical problem)

Orally disintegrating tablets are tablets that disintegrate rapidly in the mouth. In general, tablet hardness and disintegration are conflicting factors. If the hardness is increased, the disintegrability will be decreased; and if the disintegrability is increased, the hardness will be decreased. Therefore, when determining the formulation of orally disintegrating tablets, it is difficult to obtain desired hardness and disintegration at the same time.

In order to develop an orally disintegrating tablet containing various functional ingredients/granules, it is necessary to conceive some formulation design. This is because, if the ingredients/granules are uniformly dispersed in the tablet, especially if they have an adverse effect on the formability, it is necessary to add some additives in the tablet to supplement the formability of the tablet. However, the addition of additives may cause detrimental effects on the tablet (eg enlarged tablet size), so some further improvements are required.

In addition, when the inner core of a press-coated tablet comprises a powder/granular material with poor formability, the inner core has a very low hardness; therefore the outer layer surrounding the inner core needs to be stronger than that of a tablet without a core (i.e. plain tablet) or a typical compression-coated tablet with higher hardness. This has been discovered during the course of carrying out the present invention.

As a new technology for tablets, the press-coated tablets disclosed in Patent References 1 and 2 are attracting attention. In particular, Patent Reference 2 discloses an example of a formulation containing microcapsule-like particles in the inner core, and thus it is expected to use this formulation for some functional formulations such as orally disintegrating tablets. However, the press-coated tablets having an outer layer similar to that of the formulation disclosed in Patent Reference 2 had very poor oral disintegratability (see Comparative Examples 1 to 4 of the present invention). The inventors have also found that when a press-coated tablet containing granules without formability is prepared using the outer layer disclosed in patent reference 1 which involves a press-coated tablet undergoing rapid disintegration, some sufficient hardness (see Comparative Examples 1 to 5 of the present invention).

As described above, in order to prepare a press-coated tablet having a two-layer structure consisting of an inner core and an outer layer, in particular, a tablet containing granules without formability in its inner core, it is necessary to pass only Its outer layer maintains the hardness of the tablet and therefore the outer layer of the tablet needs to be harder than normal tablets. If a bilayer structure is applied to an orally disintegrating tablet, the hardness of the tablet has to be lowered so that the tablet can exhibit sufficient disintegrability. Therefore, conventional formulations and techniques for orally disintegrating tablets cannot be used without modification to provide tablets with desirable hardness and disintegrability that have poor formability for those containing Compression-coated tablets with an inner core of powder/granular material are also required.

The object of the present invention is to newly develop a press-coated tablet characterized by its inner core comprising a powder/granular material with poor formability, and to provide an excellent disintegrability and suitable tablet as a whole Compression-coated orally disintegrating tablet of hardness.

problem solution

In general, it is difficult to prepare tablets containing a large amount of granules without formability (such as functional granules), powder of active ingredients, and the like. Under such circumstances, the present inventors attempted to prepare a tablet whose inner core contains such granules or this powder and whose outer layer surrounds the inner core. In producing such a press-coated tablet comprising a powder/granular material having poor formability as described above, it is very difficult to achieve an appropriate hardness as a whole tablet while maintaining oral disintegratability. However, the present inventors studied extensively, and then found that the above-mentioned problems can be solved by using a combination of specific ingredients in the outer layer. That is, the present inventors have found that it is possible to prepare a press-coated orally disintegrating tablet with an outer layer surrounding its inner core, wherein the inner core comprises a powder/granular material with poor formability; the outer layer comprises microcrystalline cellulose, sugar or sugar alcohol and specific ingredient (c) defined below; and the compressed tablet has suitable hardness and disintegration as a whole tablet. In more detail, the present invention provides a compression-coated orally disintegrating tablet, wherein the thickness of the inner core is 30-80% of the thickness of the entire tablet, and the outer layer comprises (a) microcrystalline cellulose, (b) sugar or sugar alcohol, and (c) one or more specific ingredients selected from the group consisting of polyvinylpolypyrrolidone, starch, low-substituted hydroxypropylcellulose and carmellose; and even when the inner core has poor In terms of formability, the compressed tablet has sufficient hardness and excellent disintegration in the oral cavity.

The present invention provides various embodiments as follows.

Article 1

A compression-coated orally disintegrating tablet with an outer layer surrounding an inner core, wherein

The thickness of the inner core is 30-80% of the thickness of the whole tablet; and

The outer layer comprises (a) microcrystalline cellulose, (b) sugar or sugar alcohol, and (c) one or more types selected from the group consisting of polyvinylpolypyrrolidone, starch, low-substituted hydroxypropylcellulose and carmellose Composed of specific components of the group.

Article 2

Compression-coated orally disintegrating tablet of Bar 1, wherein the inner core is a powder/granular material with poor formability.

Article 3

The compression-coated orally disintegrating tablet of bar 1 or 2, wherein the outer layer has a porosity of 1-20%.

Bar 4

The press-coated orally disintegrating tablet of any one of items 1 to 3, wherein the inner core has a porosity of 10-90%.

Article 5

The press-coated orally disintegrating tablet of any one of items 1 to 4, wherein the content of microcrystalline cellulose (a) is 10-90 wt%, based on 100 wt% of the outer layer.

Article 6

The compression-coated orally disintegrating tablet of any one of items 1 to 5, wherein

certain ingredient (c) comprises starch, and

The starch content is 3-40wt%, based on 100wt% of the outer layer.

Article 7

The compression-coated orally disintegrating tablet of any one of items 1 to 5, wherein

The specific ingredient (c) comprises one or more ingredients selected from the group consisting of polyvinylpolypyrrolidone, low-substituted hydroxypropylcellulose and carmellose; and

The total content of the specific component (c) is 3-20wt%, based on 100wt% of the outer layer.

Article 8

The compression-coated orally disintegrating tablet of any one of items 1 to 7, wherein the sugar or sugar alcohol (b) comprises mannitol.

Article 9

The press-coated orally disintegrating tablet of any one of items 1 to 6 and 8, wherein the specific ingredient (c) comprises corn starch.

Article 10

The press-coated orally disintegrating tablet of any one of items 1 to 9, wherein the thickness of the inner core is 30-70% of the thickness of the entire tablet.

Article 11

The press-coated orally disintegrating tablet of any one of items 1 to 10, wherein the porosity of the inner core is greater than that of the outer layer.

Article 12

The press-coated orally disintegrating tablet of any one of items 1 to 11, wherein the inner core contains the active ingredient.

(invention effect)

The present invention can provide a press-coated orally disintegrating tablet characterized by an inner core comprising a powder/granular material having poor formability, which has excellent disintegrability and suitable hardness as a whole tablet.

Detailed ways

The press-coated orally disintegrating tablet of the present invention is composed of an "inner core" in which powder/granular material having poor formability such as microcapsule-like functional particles is contained, and which surrounds the inner core to give the formed tablet a suitable The hardness and disintegratability of the "outer layer" composition.

In addition, the present invention can be applied to powders with poor formability, granular materials with poor formability or powder/granular materials with poor formability in its inner core in addition to microcapsule-like functional particles To obtain tablets with sufficient hardness and disintegration.

In the present invention, the "outer layer" comprises (a) microcrystalline cellulose, (b) sugar or sugar alcohol, and (c) one or more types selected from polyvinylpolypyrrolidone, starch, low-substituted hydroxypropyl A specific component of the group consisting of cellulose and carmellose. Using a combination of these ingredients, it becomes possible to prepare a press-coated orally disintegrating tablet having sufficient hardness and excellent disintegrability as a final formulation even when the inner core contains ingredients having poor formability. The inner core, which is a powder/granular material with poor formability, preferably has a thickness of 30% or more of the thickness of the entire tablet to produce good disintegrability.

As used herein, "orally disintegrating tablet" refers to a tablet that disintegrates rapidly in the oral cavity without water. The oral disintegration time of an "orally disintegrating tablet" can be determined using a disintegration test in the human oral cavity or in a device. The orally disintegrating tablet tester used herein is, for example, ODT-101 (manufactured by Toyama Sangyo Co., Ltd.). The orally disintegrating tablet as used herein refers to a tablet whose inner core and outer layer are separated within usually 60 seconds or less, preferably 45 seconds or less, more preferably 30 seconds or less, and most preferably 20 seconds. Disintegrate or disperse in less disintegration time. In the actual disintegration test in the human oral cavity, the time from putting the tablet in the oral cavity to complete oral disintegration was measured as the oral disintegration time. After the test, the subjects removed the samples from their mouths and rinsed their mouths with water.

The value of the average particle size used herein is determined using, for example, a laser diffraction particle size analyzer manufactured by SYMPATEC (HELOS & RODOS) or manufactured by Shimadzu (SALD 3000).

The value of bulk density used herein was determined using the Constant Mass Method (Method 1) as described in the Japanese Pharmacopoeia 15th edition. Specifically, this value is calculated according to the following formula, where X cm represents the bulk volume when a sample ^, usually about 30 g, is placed in a 100 ml (cm ³ ) glass cylinder without compaction; provided that if the sample Overfilling the graduated cylinder may reduce the quality of the sample as appropriate.

Bulk density (g/cm ³ ) = sample mass (g) / X (cm ³ )

The tablet hardness of the present invention is obtained by measuring the force required to crush the tablet in the diameter direction using a tablet hardness tester (PORTABLE CHECKER PC-30, produced by Okada Seiko Co., Ltd.). "Absolute hardness" was calculated according to the following formula using the obtained tablet hardness. "Absolute hardness" is a value obtained by dividing the hardness measured using a tablet hardness tester by the longitudinal cross-sectional area (tablet diameter (mm) x tablet thickness (mm)).

Absolute hardness (N/mm ² ) = hardness (N)/longitudinal cross-sectional area (mm ² ).

The term "having suitable hardness and disintegration" as used herein means that the balance of absolute hardness and oral disintegration time is good. As an index of its balance, the term "HDBI (Hardness and Disintegrating Balance Index)" is defined according to the following formula. Larger values mean a better balance of hardness and disintegratability. Specifically, the orally disintegrating tablet of the present invention has an HDBI value of 0.15 or greater, and preferably 0.2 or greater. If the oral disintegration time is too slow or the absolute hardness is too low, the calculated value of HDBI may vary, so it is desirable to maintain the oral disintegration time of 60 seconds or less and the absolute hardness of 1N/ ^mm2 or bigger.

HDBI (N/mm ² ·sec) = absolute hardness (N/mm ² )/oral disintegration time (sec).

Generally, porosity can be calculated according to the following formula:

Tablet Porosity (%)= (1- Wt/(ρ×V))×100

ρ: true density of the tablet (mg/mm ³ ),

V: volume of the tablet (mm ³ ),

Wt: weight (mg) of the tablet.

Porosity can be measured as void ratio using, for example, a pore distribution analyzer produced by Shimadzu (Micromeritics).

In the present invention, the porosity of the outer layer can be calculated according to the following formula:

Porosity of outer layer (%)= (1-Wt/(ρ×3.14×D ² ×T))×100

ρ: true density of the outer layer (mg/mm ³ ),

D: Radius of the outer layer (under-portion) (mm),

T: thickness of the outer layer (under-portion) (mm),

Wt: Weight (under-portion) of the outer layer (mg).

In the present invention, the thickness of the inner core is calculated as follows. The thickness of the entire tablet was measured by a digital caliper (manufactured by Mitutoyo Co., Ltd.). The press-coated tablets were diametrically separated, and the cross-sectional surface was analyzed using a digital microscope (VHX-500, manufactured by Keyence Co. Ltd.) to measure the thickness of the upper and lower parts of the outer layer.

Thickness of the inner core (mm) = thickness of the entire tablet (mm) - sum of thicknesses of the upper and lower parts in the outer layer (mm)

In the present invention, the term "ratio of the thickness of the inner core" refers to the ratio of the thickness of the inner core/thickness of the entire tablet, that is, the ratio of the thickness of the inner core in a cross-sectional area parallel to the sides of the tablet. If the ratio of the thickness of the inner core depends on the separation position, the highest ratio among the entire sectional surface is defined as "the ratio of the thickness of the inner core".

The ratio of the thickness of the inner core (%) = the thickness of the inner core (mm) / the thickness of the whole tablet (mm) × 100

In the present invention, the porosity of the outer layer is preferably reduced to increase hardness compared to a general tablet without an inner core. The outer layer has a porosity of generally 1-20%, and preferably 1-15%. The inner core has a porosity of typically 10-90%, and preferably 20-80%. Generally, it is preferred that the porosity of the inner core is greater than that of the outer layer.

The invention is further exemplified below.

(1) outer layer

(a) microcrystalline cellulose

The microcrystalline cellulose used herein as an essential ingredient for the outer layer is not limited to any specific one as long as it can be orally administered. From the aspect of feeling in the oral cavity, the preferred average particle size of microcrystalline cellulose used as a raw material is 150 μm or less, more preferably 130 μm or less, and more preferably 120 μm or less, because by using a large average Formulations prepared with particle-sized microcrystalline cellulose produced a gritty texture in the oral cavity after oral disintegration.

In the press-coated orally disintegrating tablet of the present invention, the outer layer alone needs to provide sufficient hardness for the entire tablet. However, when the outer layer has a low content of microcrystalline cellulose, the hardness of the tablet is not sufficient, so the content of microcrystalline cellulose used herein is generally 10 wt% or more, based on the total weight of the outer layer of 100 wt%. count. On the other hand, from the point of view of feeling in the oral cavity, when the content of microcrystalline cellulose is too high, the tablet causes a feeling of powder, so its content used herein is usually 90 wt% or less, according to the outer layer The total weight of 100wt% meter. Considering the balance of tablet hardness and disintegration time, the content of microcrystalline cellulose is 10-90wt%, and preferably 20-70wt%, based on 100wt% of the total weight of the outer layer. Microcrystalline cellulose used herein includes, for example, CEOLUS ^™ (PH-101, PH-102, PH-301, PH-302, PH-F20J, KG-802, KG-1000, ST-02: by Asahi Kasei Chemicals Co. Ltd.) and AVICEL ^™ (PH-101, PH-102, PH-301, PH-302, FD-101, FD-301, FD-F20: produced by FMC BioPolymer Co., Ltd.). The microcrystalline cellulose used herein may be any one type of them or a combination of two or more types thereof.

The microcrystalline cellulose used herein has a bulk density of preferably 0.1 g/cm ³ to 0.5 g/cm ³ , and more preferably 0.1 g/cm ³ to 0.3 g/cm ³ . Microcrystalline cellulose having a bulk density of 0.1 g/cm ³ to 0.3 g/cm ³ includes, for example, CEOLUS KG-802 and KG-1000.

(b) sugar or sugar alcohol

The sugar or sugar alcohol used herein as an essential ingredient for the outer layer is not limited to any specific one as long as it can be orally administered; and may include natural products derived from animals or plants and by chemical synthesis or fermentation methods produced artifacts. In terms of sensation in the oral cavity, the content of sugar or sugar alcohol used herein is generally 0.5-84 wt%, preferably 20-80 wt%, and more preferably 20-75 wt%, based on the total weight of the outer layer 100 wt%.

Sugars used herein include, for example, glucose, fructose, sucrose, lactose, maltose, trehalose, and palatinose; lactose and seaweed are preferred from the viewpoint of tablet hardness and disintegrability balance. Sugar, and most preferably lactose. The sugar alcohol used herein includes, for example, erythritol, mannitol, xylitol, sorbitol, and maltitol; and erythritol and mannitol are preferable. The most preferable sugar alcohol is mannitol from the viewpoint of the balance of tablet hardness and disintegrability.

Lactose used for the outer layer herein is not particularly limited as long as it can be orally administered; and includes α-lactose monohydrate, anhydrous β-lactose, and anhydrous α-lactose. Among them, α-lactose monohydrate is preferable from the viewpoint of ease of handling. Also, lactose used as a raw material has an average particle size of preferably 150 μm or less, and more preferably 120 μm or less, from the viewpoint of feeling in the oral cavity.

Mannitol used for the outer layer herein is not particularly limited as long as it can be orally administered, and it is preferably D-mannitol. The crystal form of mannitol used herein is not particularly limited, and it may be an α-, β- or δ-form, or it may be an amorphous form obtained by using a spray-drying technique. Alternatively, the mannitol used herein may have a spherical shape and high density as disclosed in, for example, JP 11 (1999)-092403 A. Mannitol used herein has an average particle size of preferably 10 μm to 300 μm, more preferably 10 μm to 250 μm, and more preferably 30 μm to 200 μm, but is not particularly limited thereto. To obtain the desired particle size, mannitol may optionally be milled using, for example, airflow mills and hammer mills.

The most preferred sugar or sugar alcohol is mannitol in view of the sensation in the mouth. Sugar or sugar alcohol may be used alone or in combination of two or more thereof, depending on the desired formulation.

(c) specific ingredients

The specific ingredient used herein as an essential ingredient for the outer layer is characterized by at least one ingredient selected from the group consisting of polyvinylpolypyrrolidone, starch, low-substituted hydroxypropylcellulose, and carmellose. Orally disintegrating tablets without a press-coat of specific ingredients (described below) or with a press-coat of ingredients other than the above-mentioned specific ingredients for improving disintegration cannot have the desired effect , because the porosity of the outer layer of the press-coated orally disintegrating tablet needs to be reduced to increase the hardness of the outer layer compared with a normal tablet without an inner core. In contrast, the present inventors have found that the desired effect can be achieved when the outer layer comprises specific ingredients together with microcrystalline cellulose and a sugar or sugar alcohol.

(c-1) Polyvinylpolypyrrolidone

The polyvinylpolypyrrolidone used herein may be polyvinylpolypyrrolidone generally adapted to the Japanese Pharmacopoeia, but it should not be limited thereto. From the viewpoint of sensation in the oral cavity, the preferred average particle size of polyvinylpolypyrrolidone used as a raw material is, but not limited to, preferably 10 μm to 200 μm, more preferably 10 μm to 150 μm, and more preferably 10 μm to 100 μm, because Formulations prepared by using polyvinylpolypyrrolidone with a large average particle size produced a gritty texture in the oral cavity after oral disintegration. In order to obtain the desired particle size, the polyvinylpolypyrrolidone can optionally be milled with, for example, an air jet mill and a hammer mill. The content of polyvinylpolypyrrolidone is generally 3-20wt% and preferably 5-10wt%, based on the total weight of the outer layer of 100wt%.

(c-2) Starch

The starch used herein may include, for example, corn starch, potato starch, rice starch, wheat starch, sweet potato starch, mung bean starch, tapioca starch and partially pregelatinized starch; corn starch is preferred among them. In the present invention, fully pregelatinized starch cannot be used due to its poor disintegratability. These starches used herein may be any one type of them or a combination of two or more types thereof. From the aspect of feeling in the oral cavity, the average particle size of starch is, but not limited to, preferably 10 μm to 200 μm, more preferably 10 μm to 100 μm, and more preferably 10 μm to 50 μm, because the starch prepared by using starch with a large average particle size The formulation produced a gritty texture in the oral cavity after orally disintegrating. The starch may optionally be ground, for example, with air stream mills and hammer mills in order to obtain the desired particle size. From the aspects of hardness and disintegration time, the total amount of starch used herein is usually 3-40wt%, preferably 20-40wt%, based on 100wt% of the outer layer.

(c-3) Low-substituted hydroxypropyl cellulose (L-HPC)

The degree of substitution of the low-substituted hydroxypropyl cellulose of the present invention is not limited as long as it complies with the Japanese Pharmacopoeia, and the degree of substitution is usually 7.0-12.9%. From the aspect of feeling in the oral cavity, the average particle size of the low-substituted hydroxypropyl cellulose used as a raw material is, but not limited to, preferably 10 μm to 200 μm, more preferably 10 to 150 μm, more preferably 10 μm to 100 μm, because The formulation prepared by using low-substituted hydroxypropylcellulose having a large average particle size produced a gritty texture in the oral cavity after oral disintegration. In order to obtain the desired particle size, the low-substituted hydroxypropyl cellulose may optionally be milled with, for example, an air stream mill and a hammer mill. The content of low-substituted hydroxypropyl cellulose is usually 3-20wt% and preferably 5-10wt%, based on the total weight of the outer layer (100wt%).

(c-4) Carmellose (CMC)

Carmellose used herein is not particularly limited, but carmellose adapted to the Japanese Pharmacopoeia may be used herein. From the aspect of sensation in the oral cavity, the average particle size of carmellose used as a raw material is, but not limited to, preferably 10 μm to 200 μm, more preferably 10 μm to 150 μm, and more preferably 10 μm to 100 μm, because by using Formulations prepared with carmellose with a large average particle size produced a gritty texture in the oral cavity after oral disintegration. In order to obtain the desired particle size, the carboxymethylcellulose may optionally be milled using, for example, an air stream mill and a hammer mill. The content of carboxymethyl cellulose is usually 3-20wt% and preferably 5-10wt%, based on the total weight of the outer layer 100wt%.

Among the specific ingredients described above, preferred examples thereof include polyvinylpolypyrrolidone, starch, and low-substituted hydroxypropylcellulose; more preferably polyvinylpolypyrrolidone and starch; and more preferably polyvinylpolypyrrolidone and corn starch . The most preferable example of the specific ingredient is polyvinylpolypyrrolidone in view of the balance of hardness and disintegratability. If the specific ingredient used herein comprises starch and one or more specific ingredients, the total amount of the specific ingredient is usually 6-43wt% and preferably 25-40wt%, based on the total weight of the outer layer 100wt%. If the above specific ingredients other than starch are composed of two or more ingredients, the total amount of the specific ingredients other than starch is usually 6-20wt%, and preferably 6-10wt%, based on the total weight of the outer layer 100wt% .

Additional formulation ingredients

In addition to the above ingredients, additional formulation ingredients may be added to the outer layer of the orally disintegrating tablet of the present invention. As for "another formulation ingredient" in the present invention, any formulation ingredient can be used herein as long as the ingredient has no or little influence on the hardness and disintegration time of the tablet and there is no obstacle in formulation. Additional ingredients used herein include, for example, other fillers, disintegrants, binders, sweeteners, flavor/odor flavorants, stabilizers, surfactants, fluidizers, antistatic Agents, coating agents, lubricants, pigments, spices, etc. The content of "other formulation ingredients" is 0.01-25wt%, based on 100wt% of the outer layer.

lubricant

In the present invention, preferably, the tablet contains the lubricant among the above-mentioned additional formulation ingredients in its outer layer. Lubricants include, for example, stearic acid, metallic stearate, sodium stearyl fumarate, sucrose esters of fatty acids, talc, hydrogenated oils, and polyethylene glycol Diols (macrogols). Stearic acid metal salts include, for example, magnesium stearate, calcium stearate, aluminum stearate and the like. Lubricants used herein preferably include stearic acid and stearic acid metal salts, especially magnesium stearate, in terms of ease of production. On the other hand, sodium stearyl fumarate is preferable from the standpoint of the balance of hardness and disintegratability, and ease of production. The average particle size of the lubricant prior to the formulation process is 0.5 μm to 50 μm and preferably 1 μm to 30 μm. The content of the lubricant is generally 0.01-2.5 wt%, preferably 0.01-2 wt%, and more preferably 0.01-1 wt%, based on 100 wt% of the outer layer. In the present invention, the lubricant may be added to the formulation by an external lubrication method or an internal lubrication method.

(2) Inner core

In the present invention, the inner core is not limited to any specific one as long as the inner core has good oral disintegration and dispersibility. Even when the inner core of the tablet has poor formability, the outer layer of the present invention can provide sufficient hardness of the entire tablet, so the present invention is useful for the inner core containing "poor formability powder/granular material". Core tablets are also effective. "Powder/granular material with poor formability" means a powder/granular material comprising powder and/or granular material with poor formability; and this also means that it is impossible to obtain a compressed Substances or pressed substances of very low hardness. Specifically, this means that when a substance (50 mg) is compressed into a tablet (diameter 6 mm) under a pressure of 4 kN, the compressed substance cannot be obtained or a compressed substance with a very low hardness (10 N or less) is obtained even if the compression is successful. suppressed substance. From the aspect of feeling in the oral cavity, the average particle size of "powder/granular material with poor formability" used herein is, but not limited to, usually 3 mm or less, preferably 1 mm or less, more Preferably 300 μm or less, and most preferably 150 μm or less. In the present invention, it is preferred that the inner core contains the active ingredient, for example, including functional particles containing the active ingredient (such as small capsules and coated particles); powder of the active ingredient; or by adding additives to said functional particles containing the active ingredient. Granules (such as small capsules and coated granules), or powders of active ingredients are prepared by mixing powder or granular materials to improve flowability, dispersibility and adhesion.

The granular material can be obtained by, for example, fluidized bed granulation, extrusion method, drying process compression and granulation method, rotor granulation method, rotor fluidized bed granulation method, high speed mixer granulation method, and fracture granulation method. Granular method of preparation.

Functional particles containing an active ingredient can be produced according to procedures described in, for example, JP 3(1991)-130214 A, JP 2007-063263 A, WO 2005/055989, and JP 2002-332226 A. Specifically, small capsules in functional particles include, for example, microcapsules in broad terms such as microcapsules, seamless capsules, miniature soft capsules, and microspheres.

Coated particles among functional particles include, for example, polymer-coated particles, wax-coated particles, and sugar-coated particles. It also includes granules that may be inactivated by high-pressure compression, such as granules containing enzymes. Various coated particles as described above include, for example, granules prepared by coating granular particles with a coating layer, particles comprising cores in their granules, and particles prepared by coating granular particles with a coating layer. Coating Granules prepared from granules containing a core in their granules; which are designed to improve sustained release, enteric properties, gastric solubility, heat resistance, light resistance, stability or bitter taste. In the present invention, the term "coated" or "coating" includes covering the whole or part of the surface of the active ingredient with a coating material. As a device for such coating, common fluidized bed granulators (including rotor fluidized bed granulators, Wurster fluidized bed granulators, etc.) can be mentioned; in order to suppress coarsening of particles in the step, A modified Wurster fluidized bed granulator (for example, SPC, produced by POWREX CORPORATION, etc.) equipped with a device for forced circulation from the side is preferably equipped with a grinding device (screen impeller, blade stator (blade stator, cross screws, breaker, etc.) hybrid fluidized bed granulator (for example, ultrafine particle coating and granulation processing device SFP-01, produced by POWREX CORPORATION, etc. ), and a rotary fluidized bed granulator (for example, OMNITECS, produced by NARA MACHINERY CO. LTD., etc.). As an apparatus for spray drying, an ordinary spray dryer (produced by OKAWARA CORPORATION, produced by OHKAWARA KAKOKI CO. LTD., produced by Yamato, produced by Niro, etc.) can be used.

Materials for preparing the inner core of functional particles as described above include, for example, commercially available microcrystalline cellulose spheres, sucrose-starch spherical particles, purified sucrose spherical particles, lactose-crystalline cellulose spherical particles, D -Mannitol, calcium hydrogen phosphate dehydrate, magnesium oxide, magnesium hydroxide, etc.

active ingredient

The active ingredient used in the orally disintegrating tablet of the present invention is not limited to any specific one as long as the active ingredient is used as a pharmaceutical active ingredient for treating and preventing diseases and is orally administrable. Active ingredients include, for example, alimentary roborants; antipyretic analgesic antiphlogistics; psychotropic agents; hypnotics; antispasmodics; central nervous system acting drugs (central nervous system acting drugs); cerebral metabolism improving agents; cerebral circulation improving agents; antiepileptics; sympathomimetics; digestants Antiulcer Agents; Prokinetic Agents; Antacids; Antitussive Expectorants; Antimotility Agents; Antiemetics; Respiratory Stimulant Respiratory stimulants; bronchodilators; antiallergic agents; cardiac agents; antiarrhythmic agents; diuretics; vasoconstrictors; coronary artery Coronary Vasodilators; Vasodilator Agents; Peripheral Vasodilators; Antihyperlipemic Drugs; Cholegogues; Chemotherapeutics; For Diabetes Drugs for diabetic complications; osteoporosis treating drugs; antirheumatics; skeletal muscle relaxants; gout suppressants; anticoagulants agent (anticoagulants); antineoplastic agent (an tineoplastic agents) and so on. The active ingredient used herein may be in its salt or free form as long as it is pharmaceutically acceptable. It may also be in the form of solvates such as alcoholates and hydrates. Also, the above active ingredients may be used alone or in combination of two or more types thereof.

When the core of the present invention contains an active ingredient, the content of the active ingredient in the core is, but not particularly limited to, 0.1-100wt% and preferably 1-95wt%, based on 100wt% of the inner core. The "active ingredient content in the inner core" in the present invention is based on the form of the "pharmaceutical active ingredient" usually used as a drug, that is, in the case of a drug in the form of a salt, it is based on the amount of the salt. Also, the above active ingredients may be added to the outer layer to such an extent that they have no or little effect on the hardness and oral disintegration time of the final formulation.

(3) Method for compression-coated orally disintegrating tablet

The press-coated orally disintegrating tablet of the present invention can be produced using a known tablet press capable of producing press-coated formulations. A press-coated orally disintegrating tablet containing a large amount of microcapsule-like functional particles in its inner core can use the tablet press disclosed in WO 2005/097041, etc. Compression-coated formulations of poorly formable cores are produced on similar tablet presses or methods.

The laboratory procedure for the compression-coated orally disintegrating tablet of the present invention included the following:

The mixture of ingredients (a) to (c) as described above was placed in a mold with a diameter corresponding to the diameter of the desired inner core, and the mold was shaken gently to smooth the surface of the powder (which is the lower part of the outer layer). On the mixture, an appropriate amount of powder/granular material having poor formability as a component for the inner core is placed, and the layered material is temporarily pressed at a lower pressure using a manual press. This temporarily compressed mass is placed concentrically on a punch having a diameter corresponding to that of the final formulation in such a way that the lower part of the outer layer is placed downwards. A mold is laid over it, and an appropriate amount of additional mixture of the above-mentioned outer layer ingredients (for the sides and upper part of the outer layer) is placed on the temporarily compressed mass. The composition between the die and punch is finally compressed into tablets to make press-coated orally disintegrating tablets.

Another example of a procedure includes the following:

The mixture of ingredients (a) to (c) as described above is placed into a mold having a diameter corresponding to the desired tablet diameter and temporarily compressed using a hand press at low pressure. In addition, a powder/granular material with poor formability as a component for the inner core is placed in a mold having a diameter corresponding to that of the inner core and temporarily pressed at a lower pressure using a manual press. The temporarily compressed substance for the inner core is placed concentrically on the above-mentioned temporarily compressed material for the outer layer. The mold is covered thereon, and an appropriate amount of additional mixture of the above outer layer ingredients is placed on the temporarily compressed mass. The composition between the die and punch is finally compressed into tablets to make press-coated orally disintegrating tablets.

The material of the outer layer can be prepared as granules according to methods known in the art prior to tabletting. For example, a press-coated formulation can be prepared as described above using a homogeneous mixture of ingredients (a) to (c) above. Also, each of the above-mentioned ingredients (a) to (c) is granulated before tableting, a lubricant is added to the mixture of the granulated ingredients, and then a compressed tablet can be prepared as described above using the obtained mixture. Coated formulations. Also, a part of each of the ingredients (a) to (c) above is granulated before tableting, and the remaining ingredients of (a) to (c) and a lubricant are added to the mixture of the granulated ingredients, and then A compression-coated formulation can be prepared as described above using the obtained mixture. Granulation methods include, for example, fluidized bed granulation, extrusion, drying process compression and granulation methods, rotor granulation methods, rotor fluidized bed granulation methods, high-speed mixing/granulation methods, and fracture granulation methods .

(4) Compression-coated orally disintegrating tablets

The press-coated orally disintegrating tablet prepared as described above refers to a preparation that can be administered without water and exhibits rapid disintegration in the oral cavity. Specifically, the orally disintegrating tablet of the present invention refers to a preparation that is orally disintegrated mainly by saliva within about 60 seconds, usually 45 seconds, preferably 30 seconds, and more preferably 20 seconds.

Moreover, the orally disintegrating tablet of the present invention has sufficient hardness to avoid chipping or cracking during production, transportation, or clinical practice. If several drugs are given to a patient, in order to improve drug compliance, hospitals or pharmacies now often provide all-in-one packages in which each package contains several drugs for each dose to prevent patients from forgetting to take their medicines or making mistakes in taking their medicines. In order to handle tablets in this manner, it is also desirable that the tablets have sufficient hardness to avoid chipping or cracking. In particular, the orally disintegrating tablet of the present invention has a double-layer structure, which makes the tablet more likely to crumble or crack than conventional orally disintegrating tablets, so it is desirable that the tablet of the present invention be harder than conventional tablets. Specifically, the orally disintegrating tablet of the present invention has an absolute hardness of 2.0 N/mm ² or more, and preferably 2.5 N/mm ² or more.

The shape of the compression-coated orally disintegrating tablet of the final formulation of the present invention may be, but not particularly limited to, round tablet, round R-tablet, round with angular corners Shaped tablets, tablets of various irregular shapes, etc. The diameter of the round tablet, round R-tablet, and round beveled edge tablet of the present invention is usually 5 mm to 16 mm, and preferably 7 mm to 10 mm.

In the present invention, "the ratio of the thickness of the inner core" is usually 30-80%, preferably 30-70%, and more preferably 30-60%. The thickness of the outer layer used herein is usually 0.5 mm to 2.0 mm, preferably 0.5 mm to 1.5 mm, and more preferably 0.5 mm to 1.0 mm.

In the present invention, the volume percentage of the inner core, based on 100% of the final formulation, is 10-60% and preferably 15-50%.

The press-coated orally disintegrating tablet of the present invention should satisfy disintegrability in the oral cavity and sufficient hardness to maintain its form as a preparation when handled in the production process, distribution process, clinical practice and the like. It is required that the outer layer has sufficient hardness, since it is a feature of the present invention that the formulation of the present invention contains a powder/granular material having poor formability as its inner core. In addition, a higher hardness of the outer layer is necessary compared to conventional orally disintegrating tablets without a core. A lower porosity of the outer layer is preferred compared to conventional tablets so that sufficient hardness can be achieved. The outer layer of the tablet has a porosity of preferably 1-20% and more preferably 1-15%.

Example

Hereinafter, the present invention is further illustrated by the following examples, but the present invention should not be construed as being limited thereto.

Unless otherwise specified, the mannitol used in the examples; lactose; sodium stearyl fumarate; corn starch; magnesium stearate; carmellose; low-substituted hydroxypropyl cellulose (L-HPC ); microcrystalline cellulose spheres; microcrystalline cellulose and polyvinylpolypyrrolidone as follows:

Mannitol (Pearlitol 50C; manufactured by ROQUETTE);

Lactose hydrate (Pharmatose 200M: manufactured by DMV International);

Sodium octadecyl fumarate (PRUV: manufactured by Kimura Sangyo Co., Ltd.);

Corn starch [(XX16)W: produced by Nihon Shokuhin Kako Co., Ltd.];

Magnesium stearate (light and vegetable: manufactured by Taihei Chemical Industrial Co., Ltd.);

Carmellose (NS-300: produced by Gotoku Chemical Co., Ltd.);

Low-substituted hydroxypropylcellulose (LH-21: produced by Shin-Etsu Chemical Co., Ltd.);

Microcrystalline cellulose spheres (CELPHERE® CP-203: produced by Asahi KASEI Chemicals Co., Ltd.);

Microcrystalline cellulose (CEOLUS® PH-101 or CEOLUS® PH-301, CEOLUS® KG-802, CEOLUS® KG-1000: all manufactured by Asahi KASEI Chemicals Co. Ltd.); and

Polyvinylpolypyrrolidone (KOLLIDON® CL: produced by BASF Japan Ltd., or Polyplasdone XL-10: produced by ISP Japan Ltd.).

Examples 1-1 to 1-5: Studies of specific components

<Preparation of press-coated orally disintegrating tablet>

Five formulations were prepared according to the formulation shown in Table 1-1, wherein each specific component in the outer layer was different from each other. First, mix the ingredients for each outer layer. A portion (40 mg) of each mixture was placed in a mold (diameter 6 mm) and the mold was shaken gently to smooth the surface of the powder (which is the lower part of the outer layer). On the mixture, 50 mg of microcrystalline cellulose spheres (CELPHERE, CP-203) as an ingredient for the inner core were placed, and then temporarily pressed under low pressure (3 kN) using a manual press (oil press system, produced by RIKEN) The layered material is pressed. The temporarily pressed mass was placed concentrically on a punch (8 mm in diameter) in such a way that the lower part of the outer layer lay down. A mold (diameter 8 mm) was overlaid and an additional mixture of the above-mentioned outer layer ingredients (for the sides and upper part of the outer layer, 140 mg) was placed on top of the temporarily compressed mass. The composition between the punch and the die is finally compressed at a pressure of 15kN in Examples 1-2 and 1-5, and in other examples at 10kN to make the desired press-coated orally disintegrating tablet . Furthermore, the hardness of the compressed tablet (50 mg) prepared by compressing only microcrystalline cellulose spheres (CELPHERE CP-203) used here under a pressure of 4 kN in a punch/die (diameter 6 mm) was less than 10 N.

Table 1-1: Formula (mg)

the the Example 1-1 Example 1-2 Example 1-3 Example 1-4 Example 1-5 Inner core Microcrystalline Cellulose Balls (CELPHERE CP-203) 50.0 50.0 50.0 50.0 50.0 outer layer D-mannitol 131.4 131.4 131.4 131.4 - outer layer lactose - - - - 131.4 outer layer corn starch 9.0 - - - - outer layer polyvinylpolypyrrolidone - 9.0 - - 9.0 outer layer Carmellose - - 9.0 - - outer layer L-HPC (LH-21) - - - 9.0 - outer layer Microcrystalline Cellulose (KG-802) 36.0 36.0 36.0 36.0 36.0 outer layer Sodium Octadecyl Fumarate 3.6 3.6 3.6 3.6 3.6 the total 230.0 230.0 230.0 230.0 230.0

Table 1-2. The preparation ratio in the outer layer (wt%)

the the Example 1-1 Example 1-2 Example 1-3 Example 1-4 Example 1-5 outer layer D-mannitol 73.0 73.0 73.0 73.0 - outer layer lactose - - - - 73.0 outer layer corn starch 5.0 - - - - outer layer polyvinylpolypyrrolidone - 5.0 - - 5.0 outer layer Carmellose - - 5.0 - - outer layer L-HPC (LH-21) - - - 5.0 - outer layer Microcrystalline Cellulose (KG-802) 20.0 20.0 20.0 20.0 20.0 outer layer Sodium Octadecyl Fumarate 2.0 2.0 2.0 2.0 2.0 the total 100.0 100.0 100.0 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Tables 1-3 to show the physical properties of the product tablets. Tablets prepared in Examples 1-1 to 1-4, which contain any of carmellose, cornstarch, L-HPC or polyvinylpolypyrrolidone in their outer layers, for 30 seconds or less Oral disintegration time, absolute hardness of 2.0 N/mm ² or greater, and high value of HDBI (which is an indicator of the balance of hardness and disintegrability). Also, all formulations had a good feel in the mouth and were not drying. In all of these formulations, the measured porosity of the lower portion of the outer layer was 20% or less. In the case of formulations containing polyvinylpolypyrrolidone as a specific ingredient (Examples 1-2), the value of HDBI is the highest. And, even when the mannitol used in Example 1-2 was replaced by lactose as in Example 1-5, the tablet of Example 1-5 also achieved an oral disintegration time of 30 seconds or less, 2.0 Absolute hardness of N/mm ² or more, and high numerical value of HDBI (which is an index of balance of hardness and disintegratability).

Table 1-3. Tablet Physical Properties

the Example 1-1 Example 1-2 Example 1-3 Example 1-4 Example 1-5 Oral disintegration time (seconds) 14 14 15 15 17 Absolute hardness (N/mm ² ) 2.1 2.9 2.2 2.4 3.9 HDBI 0.15 0.21 0.15 0.16 0.23

Comparative Examples 1-1 to 1-3: Tablets without specific ingredients or microcrystalline cellulose (Case 1)

Several preparations were prepared in the same manner as in Example 1-1 according to the formulation shown in Table 2-1, wherein their outer layers lacked specific ingredients or microcrystalline cellulose. The mannitol used here was Mannite S (manufactured by Towa Kasei Co., Ltd.). The final compression into tablets was performed at a pressure of 4 kN and 15 kN in Comparative Examples 1-1 and 1-2, and at a pressure of 15 kN in Comparative Examples 1-3.

Table 2-1. Formulation (mg)

the the Comparative example 1-1 Comparative example 1-2 Comparative example 1-3 Inner core Microcrystalline Cellulose Balls (CELPHERE CP-203) 50.0 50.0 50.0 outer layer lactose 45.0 - - outer layer D-mannitol - 45.0 159.7 outer layer corn starch - - 16.7 outer layer Microcrystalline Cellulose (PH-102) 133.9 133.9 - outer layer Magnesium stearate 1.1 1.1 - outer layer Sodium Octadecyl Fumarate - - 3.6 the total 230.0 230.0 230.0

Table 2-2. The preparation ratio in the outer layer (wt%)

the the Comparative example 1-1 Comparative example 1-2 Comparative example 1-3 outer layer lactose 25.0 - - outer layer D-mannitol - 25.0 88.7 outer layer corn starch - - 9.3 outer layer Microcrystalline Cellulose (PH-102) 74.4 74.4 - outer layer Magnesium stearate 0.6 0.6 - outer layer Sodium Octadecyl Fumarate - - 2.0 the total 100.0 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Tables 2-3 to show the physical properties of the product tablets. Tablets prepared in Comparative Examples 1-1 to 1-3 lacked the specific ingredients of the present invention or microcrystalline cellulose in their outer layers; although the tablets of Comparative Example 1-1 barely managed to achieve 30 seconds or less The oral disintegration time and the absolute hardness of 2.0 N/mm ² or more, the tablets of other comparative examples have low absolute hardness. In particular, all tablets in the comparative examples had low HDBI values, ie less than 0.1, where HDBI signifies the balance of hardness and disintegration.

Table 2-3. Physical Properties of Tablets

the Comparative example 1-1 Comparative example 1-2 Comparative example 1-3 Oral disintegration time (seconds) 28 16 15 Absolute hardness (N/mm ² ) 2.0 1.3 1.4 HDBI 0.07 0.08 0.09

Comparative Examples 1-4: Tablets without specific ingredients (i.e., tablets with the outer layer of Patent Reference 2) (Case 2)

Preparations were prepared in the same manner as in Example 1-1 according to the formulations shown in Tables 2-4 (i.e., formulations similar to those of the formulation examples in Patent Reference 2), wherein its outer layer did not contain the specific compound of the present invention. ingredients etc. Final compression into tablets was performed at a pressure of 10 kN. Note that a small amount of magnesium stearate was applied in the dies and punches used here. Cellactose 80 used here is produced by MEGGLE Co., Ltd.

Table 2-4. Formula (mg)

the the Comparative example 1-4 Inner core Microcrystalline Cellulose (CELPHERE CP-203) 50.00 outer layer Cellactose 80 (granulated product of lactose and powdered cellulose) 180.00 outer layer Magnesium stearate trace the total 230.0

Table 2-5. The preparation ratio in the outer layer (wt%)

the the Comparative example 1-4 outer layer Cellactose 80 (granulated product of lactose and powdered cellulose) 100.0 outer layer Magnesium stearate trace the total 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Tables 2-6 to show the physical properties of the product tablets. Product tablets do not disintegrate in the mouth.

Table 2-6. Tablet Physical Properties

the Comparative example 1-4 Oral disintegration time (seconds) 120 or more Absolute hardness (N/mm ² ) 3.7 HDBI 0.03 or lower

Comparative Examples 1-5: Tablets without specific ingredients (i.e., tablets with the outer layer of Patent Reference 1) (Case 3)

Preparations were prepared in the same manner as in Example 1-1 according to the formulations shown in Tables 2-7, wherein the outer layer thereof did not contain the specific ingredients of the present invention. Final compression into tablets was performed at a pressure of 10 kN. The components of the outer layer used here and their ratios are the same as those used in Test Example 6 of Patent Reference 1 (60 mg of erythritol, 19.5 mg of microcrystalline cellulose, and 0.5 mg of stearin Magnesium acid).

Table 2-7. Formulation (mg)

the the Comparative example 1-5 Inner core Microcrystalline Cellulose Balls (CELPHERE CP-203) 50.00 outer layer Erythritol (sugar) alcohol 135.00 outer layer Microcrystalline Cellulose (CEOLUS PH-102) 43.90 outer layer Magnesium stearate 1.10 the total 230.0

Table 2-8. The preparation ratio in the outer layer (wt%)

the the Comparative example 1-5 outer layer Erythritol (sugar) alcohol 75.0 outer layer Microcrystalline Cellulose (CEOLUS PH-102) 24.4 outer layer Magnesium stearate 0.6 the total 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Tables 2-9 to show the physical properties of the product tablets. When a press-coated tablet comprising unformable granules was prepared using the outer layer described in Test Example 6 of Patent Reference 1, its oral disintegration time was rapid, but its absolute hardness was insufficient and low (i.e. , less than 1N/mm ² ).

Therefore, it is inferred that when the composition of the outer layer disclosed in Patent Reference 1 is used to prepare a press-coated tablet whose inner core contains granules that do not have formability, the prepared tablet cannot be provided for the whole tablet. sufficient hardness.

Table 2-9. Tablet Physical Properties

the Comparative example 1-5 Oral disintegration time (seconds) 12 Absolute hardness (N/mm ² ) 0.4 HDBI 0.03

Examples 2-1 to 2-6 and Comparative Example 2-1: Ratio of microcrystalline cellulose

Several preparations were prepared in the same manner as in Example 1-1 according to the formulation shown in Table 3-1, wherein the respective amounts of microcrystalline cellulose in the outer layer were different from each other. Final compression into tablets at a pressure of 15 kN in Comparative Example 2-1 and Examples 2-1 to 2-3, 10 kN in Example 2-4, and 4 kN in Examples 2-5 and 2-6 conduct.

Table 3-1. Formula (mg)

the the Comparative example 2-1 Example 2-1 Example 2-2 Example 2-3 Example 2-4 Example 2-5 Example 2-6 Inner core Microcrystalline Cellulose (CELPHERE CP-203) 50.0 50.0 50.0 50.0 50.0 50.0 50.0 outer layer D-mannitol 165.6 149.4 131.4 113.4 95.4 41.4 0.9 outer layer polyvinylpolypyrrolidone 9.0 9.0 9.0 9.0 9.0 9.0 14.4 outer layer Microcrystalline Cellulose (KG-802) - 18.0 36.0 54.0 72.0 126.0 161.1 outer layer Microcrystalline Cellulose (KG-1000) 1.8 - - - - - - outer layer Sodium Octadecyl Fumarate 3.6 3.6 3.6 3.6 3.6 3.6 3.6 the total 230.0 230.0 230.0 230.0 230.0 230.0 230.0

Table 3-2. The preparation ratio in the outer layer (wt%)

the the Comparative example 2-1 Example 2-1 Example 2-2 Example 2-3 Example 2-4 Example 2-5 Example 2-6 outer layer D-mannitol 92.0 83.0 73.0 63.0 53.0 23.0 0.5 outer layer polyvinylpolypyrrolidone 5.0 5.0 5.0 5.0 5.0 5.0 8.0 outer layer Microcrystalline Cellulose (KG-802) - 10.0 20.0 30.0 40.0 70.0 89.5 outer layer Microcrystalline Cellulose (KG-1000) 1.0 - - - - - - outer layer Sodium octadecyl fumarate 2.0 2.0 2.0 2.0 2.0 2.0 2.0 the total 100.0 100.0 100.0 100.0 100.0 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 3-3 to show the physical properties of the product tablets. As in Comparative Example 2-1, when the content of microcrystalline cellulose in the outer layer was 1%, the tablet had an absolute hardness of less than 2.0 N/mm ² and a low value of HDBI (which is hardness and disintegrability indicator of balance). In contrast, as in Examples 2-1 to 2-6, when the content of microcrystalline cellulose in the outer layer was 10-90%, the tablet achieved an oral disintegration time of 30 seconds or less, 2.0 N/mm An absolute hardness of ² or greater, and a high value of HDBI (which is an indicator of the balance of hardness and disintegratability).

From the viewpoint of feeling in the oral cavity, the preferred content of microcrystalline cellulose in the outer layer is 70% or less, because a tablet with a high content thereof has a sandy texture when administered. On the other hand, from the viewpoint of hardness, the preferred content of microcrystalline cellulose in the outer layer is 20% or more because these tablets have an absolute hardness of 2.5 N/mm ² or more. Also, the tablet reached the highest value of HDBI (which is an indicator of the balance of hardness and disintegratability) with a content of microcrystalline cellulose in the outer layer of 20-30%.

Table 3-3. Physical Properties of Tablets

the Comparative example 2-1 Example 2-1 Example 2-2 Example 2-3 Example 2-4 Example 2-5 Example 2-6 Oral disintegration time (seconds) 11 11 14 15 19 20 28 Absolute hardness (N/mm ² ) 1.2 2.0 2.9 3.2 3.5 3.3 4.1 HDBI 0.11 0.19 0.21 0.21 0.18 0.17 0.15

Examples 3-1 to 3-2 and Comparative Examples 3-1 to 3-2: Proportions of specific ingredients (polyvinylpolypyrrolidone)

Several preparations were prepared in the same manner as in Example 1-1 according to the formulation shown in Table 4-1, wherein each amount of polyvinylpolypyrrolidone in the outer layer was different from each other. Final compression into tablets was performed at a pressure of 15 kN in Comparative Example 3-1 and Example 3-1, at 10 kN in Example 3-2, and at a pressure of 4 kN in Comparative Example 3-2.

Table 4-1. Formula (mg)

the the Comparative example 3-1 Example 3-1 Example 3-2 Comparative example 3-2 Inner core Microcrystalline Cellulose (CELPHERE CP-203) 50.0 50.0 50.0 50.0 outer layer D-mannitol 156.6 131.4 122.4 68.4 outer layer polyvinylpolypyrrolidone 1.8 9.0 36.0 72.0 outer layer Microcrystalline Cellulose (KG-802) 18.0 36.0 18.0 36.0 outer layer Sodium Octadecyl Fumarate 3.6 3.6 3.6 3.6 the total 230.0 230.0 230.0 230.0

Table 4-2. The preparation ratio in the outer layer (wt%)

the the Comparative example 3-1 Example 3-1 Example 3-2 Comparative example 3-2 outer layer D-mannitol 87.0 73.0 68.0 38.0 outer layer polyvinylpolypyrrolidone 1.0 5.0 20.0 40.0 outer layer Microcrystalline Cellulose (KG-802) 10.0 20.0 10.0 20.0 outer layer Sodium Octadecyl Fumarate 2.0 2.0 2.0 2.0 the total 100.0 100.0 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 4-3 to show the physical properties of the product tablets. As in Examples 3-1 and 3-2, when the content of polyvinylpolypyrrolidone in the outer layer is 5-20%, the tablet achieves an oral disintegration time of 30 seconds or less, 2.0 N/mm ² or Greater absolute hardness, and high values of HDBI (which is an indicator of the balance of hardness and disintegratability). On the contrary, as in Comparative Examples 3-1 and 3-2, when the content of polyvinylpolypyrrolidone in the outer layer was too low (ie 1%) or too high (ie 40%), any one of the tablets had a low value HDBI (which is an indicator of the balance of hardness and disintegratability).

Table 4-3. Physical Properties of Tablets

the Comparative example 3-1 Example 3-1 Example 3-2 Comparative example 3-2 Oral disintegration time (seconds) twenty one 14 19 27 Absolute hardness (N/mm ² ) 2.2 2.9 2.8 2.4 HDBI 0.10 0.21 0.15 0.09

Examples 4-1 to 4-2 and Comparative Example 4-1: Proportions of specific ingredients (corn starch)

Several preparations were prepared in the same manner as in Example 1-1 according to the formulation shown in Table 5-1, wherein each amount of cornstarch in the outer layer was different from each other. Final compression into tablets was performed at a pressure of 10 kN in Comparative Example 4-1 and Example 4-1, and at a pressure of 15 kN in Example 4-2.

Table 5-1. Formula (mg)

the the Comparative example 4-1 Example 4-1 Example 4-2 Inner core Microcrystalline Cellulose (CELPHERE CP-203) 50.0 50.0 50.0 outer layer D-mannitol 120.6 131.4 50.4 outer layer corn starch 1.8 9.0 72.0 outer layer Microcrystalline Cellulose (KG-802) 54.0 36.0 54.0 outer layer Sodium Octadecyl Fumarate 3.6 3.6 3.6 the total 230.0 230.0 230.0

Table 5-2. The preparation ratio in the outer layer (wt %)

the the Comparative example 4-1 Example 4-1 Example 4-2 outer layer D-mannitol 67.0 73.0 28.0 outer layer corn starch 1.0 5.0 40.0 outer layer Microcrystalline Cellulose (KG-802) 30.0 20.0 30.0 outer layer Sodium Octadecyl Fumarate 2.0 2.0 2.0 the total 100.0 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 5-3 to show the physical properties of the product tablets. As in Examples 4-1 and 4-2, when the content of cornstarch in the outer layer is 5-40%, the tablet achieves an oral disintegration time of 30 seconds or less, 2.0 N/mm ² or more Absolute hardness of , and a high value of HDBI (which is an indicator of the balance of hardness and disintegratability). On the contrary, as in Comparative Example 4-1, when the content of cornstarch in the outer layer was too low (i.e. 1%), the tablet had a slow oral disintegration time of at least 30 seconds, and the same low value of HDBI (its is an indicator of the balance between hardness and disintegration).

Table 5-3. Tablet Physical Properties

the Comparative example 4-1 Example 4-1 Example 4-2 Oral disintegration time (seconds) 38 15 20 Absolute hardness (N/mm ² ) 3.1 2.1 3.4 HDBI 0.08 0.15 0.17

Examples 5-1 to 5-4: Types of microcrystalline cellulose

Several preparations were prepared in the same manner as in Example 1-1 according to the formulation shown in Table 6-1, wherein each type of microcrystalline cellulose in the outer layer was different from each other. Final compression into tablets was performed at a pressure of 15 kN.

Table 6-1. Formula (mg)

the the Example 5-1 Example 5-2 Example 5-3 Example 5-4 Inner core Microcrystalline Cellulose (CELPHERE CP-203) 50.0 50.0 50.0 50.0 outer layer D-mannitol 131.4 131.4 131.4 149.4 outer layer polyvinylpolypyrrolidone 9.0 9.0 9.0 9.0 outer layer Microcrystalline Cellulose (KG-802) 36.0 - - - outer layer Microcrystalline Cellulose (PH-102) - 36.0 - - outer layer Microcrystalline Cellulose (PH-301) - - 36.0 - outer layer Microcrystalline Cellulose (KG-1000) - - - 18.0 outer layer Sodium Octadecyl Fumarate 3.6 3.6 3.6 3.6 the total 230.0 230.0 230.0 230.0

Table 6-2. The preparation ratio in the outer layer (wt %)

the the Example 5-1 Example 5-2 Example 5-3 Example 5-4 outer layer D-mannitol 73.0 73.0 73.0 83.0 outer layer polyvinylpolypyrrolidone 5.0 5.0 5.0 5.0 outer layer Microcrystalline Cellulose (KG-802) 20.0 - - - outer layer Microcrystalline Cellulose (PH-102) - 20.0 - - outer layer Microcrystalline Cellulose (PH-301) - - 20.0 - outer layer Microcrystalline Cellulose (KG-1000) - - - 10.0 outer layer Sodium Octadecyl Fumarate 2.0 2.0 2.0 2.0 the total 100.0 100.0 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 6-3 to show the physical properties of the product tablets. Although each type of microcrystalline cellulose in the outer layer was different as in Examples 5-1 to 5-4, all tablets achieved an oral disintegration time of 30 seconds or less, 2.0 N/mm ² or more Absolute hardness of , and a high value of HDBI (which is an indicator of the balance of hardness and disintegratability). When KG-802 or KG-1000 is used as the microcrystalline cellulose of outer layer, any one tablet reaches 0.2 or greater HDBI value (wherein HDBI is the index of the balance of hardness and disintegratability) to obtain having preferred Balanced tablet.

Table 6-3. Physical Properties of Tablets

the Example 5-1 Example 5-2 Example 5-3 Example 5-4 Oral disintegration time (seconds) 14 11 12 12 Absolute hardness (N/mm ² ) 2.9 2.1 2.0 2.3 HDBI 0.21 0.19 0.17 0.20

Examples 6-1 to 6-3: Types of lubricants

Several formulations were prepared in the same manner as in Example 1-1 according to the formulation shown in Table 7-1, wherein each type of lubricant in the outer layer was different from each other. Final compression into tablets was performed at a pressure of 15 kN.

Table 7-1. Formula (mg)

the the Example 6-1 Example 6-2 Example 6-3 Inner core Microcrystalline Cellulose (CELPHERE CP-203) 50.0 50.0 50.0 outer layer D-mannitol 131.4 133.2 133.2 outer layer polyvinylpolypyrrolidone 9.0 9.0 9.0 outer layer Microcrystalline Cellulose (KG-802) 36.0 36.0 36.0 outer layer Sodium Octadecyl Fumarate 3.6 - - outer layer Sucrose Fatty Acid Ester - 1.8 - outer layer Magnesium stearate - - 1.8 the total 230.0 230.0 230.0

Table 7-2. The preparation ratio in the outer layer (wt %)

the the Example 6-1 Example 6-2 Example 6-3 outer layer D-mannitol 73.0 74.0 74.0 outer layer polyvinylpolypyrrolidone 5.0 5.0 5.0 outer layer Microcrystalline Cellulose (KG-802) 20.0 20.0 20.0 outer layer Sodium Octadecyl Fumarate 2.0 - - outer layer Sucrose Fatty Acid Ester - 1.0 - outer layer Magnesium stearate - - 1.0 the total 100.0 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 7-3 to show the physical properties of the product tablets. Although, as in Examples 6-1 to 6-3, the respective types of lubricants in the outer layer were different, all the tablets achieved an oral disintegration time of 30 seconds or less, an absolute of 2.0 N/mm ² or more Hardness, and high values of HDBI (which is an indicator of the balance of hardness and disintegratability).

Table 7-3. Physical Properties of Tablets

the Example 6-1 Example 6-2 Example 6-3 Oral disintegration time (seconds) 14 13 15 Absolute hardness (N/mm ² ) 2.9 4.0 2.8 HDBI 0.21 0.30 0.19

Examples 7-1 to 7-5: Combining several specific ingredients

Several preparations were prepared in the same manner as in Example 1-1 according to the formulation shown in Table 8-1, wherein two or more specific ingredients were contained in the outer layer. Final compression into tablets was performed at a pressure of 10 kN in Examples 7-1 and 7-3, and 15 kN in other examples.

Table 8-1. Formula (mg)

the the Example 7-1 Example 7-2 Example 7-3 Example 7-4 Example 7-5 Inner core Microcrystalline Cellulose (CELPHERE CP-203) 50.0 50.0 50.0 50.0 50.0 outer layer D-mannitol 113.4 113.4 66.6 134.5 118.3 outer layer corn starch 18.0 18.0 36.0 14.9 13.1 outer layer polyvinylpolypyrrolidone - - - 9.0 9.0 outer layer Carmellose 3.6 3.6 7.2 - - outer layer L-HPC (LH-21) 7.2 7.2 14.4 - - outer layer Microcrystalline Cellulose (KG-802) - 36.0 - 18.0 36.0 outer layer Microcrystalline Cellulose (KG-1000) 36.0 - 54.0 - - outer layer Sodium Octadecyl Fumarate - - - 3.6 3.6 outer layer Magnesium stearate 1.8 1.8 1.8 - - the total 230.0 230.0 230.0 230.0 230.0

Table 8-2. The preparation ratio in the outer layer (wt %)

the the Example 7-1 Example 7-2 Example 7-3 Example 7-4 Example 7-5 outer layer D-mannitol 63.0 63.0 37.0 74.7 65.7 outer layer corn starch 10.0 10.0 20.0 8.3 7.3 outer layer polyvinylpolypyrrolidone - - - 5.0 5.0 outer layer Carmellose 2.0 2.0 4.0 - - outer layer L-HPC (LH-21) 4.0 4.0 8.0 - - outer layer Microcrystalline Cellulose (KG-802) - 20.0 - 10.0 20.0 outer layer Microcrystalline Cellulose (KG-1000) 20.0 - 30.0 - - outer layer Sodium Octadecyl Fumarate - - - 2.0 2.0 outer layer Magnesium stearate 1.0 1.0 1.0 - - the total 100.0 100.0 100.0 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 8-3 to show the physical properties of the product tablets. Even in the case where the outer layer contains two or more specific ingredients, the tablet achieves an oral disintegration time of 30 seconds or less, an absolute hardness of 2.0 N/mm ² or more, and a high value of HDBI ( It is an indicator of the balance of hardness and disintegratability). The porosity of the outer layer was 9% in Example 7-1 and 10% in Example 7-3.

Table 8-3. Physical Properties of Tablets

the Example 7-1 Example 7-2 Example 7-3 Example 7-4 Example 7-5 Oral disintegration time (seconds) 15 18 20 11 13 Absolute hardness (N/mm ² ) 2.2 2.7 3.2 2.2 2.8 HDBI 0.15 0.15 0.16 0.19 0.21

Examples 8-1 to 8-2: Thickness ratio of inner core

Two formulations were prepared according to the formulation shown in Table 9-1, in which the thickness ratios of the respective inner cores were different from each other. First, mix the ingredients for the outer layer. The mixture of outer layers in the amount indicated in each "Weight of outer layer (lower)" column in Table 9-1 was placed in a mold having the diameter indicated in each "Inner core" column in Table 9-1. Shake the mold gently to smooth the surface of the powder. On the mixture, microcrystalline cellulose spheres (CELPHERE CP-203) in the number shown in the table were placed, and the layered material was temporarily pressed under a low pressure of 3 kN using a manual press (oil press system, produced by RIKEN). The temporarily pressed mass was placed concentrically on a punch (8 mm in diameter) in such a way that the lower part of the outer layer lay down. A mold (diameter 8 mm) was placed thereon and additional mixtures of the above-mentioned outer layer ingredients were added therein in the amounts indicated in the respective "weight of outer layer (side and upper)" columns in Table 9-1. The composition between the die and the punch is finally compressed to make a press-coated orally disintegrating tablet. Final compression into tablets was performed at a pressure of 4 kN.

Table 9-1. Formula (mg)

the the Example 8-1 Example 8-2 structure Inner core diameter 6 mm diameter 6 mm structure Weight of outer layer (lower part) 40mg 30mg structure Weight of outer layers (side and upper) 140mg 110mg Inner core Microcrystalline Cellulose (CELPHERE CP-203) 50.00 50.00 outer layer D-mannitol 41.40 41.40 outer layer polyvinylpolypyrrolidone 9.00 9.00 outer layer Microcrystalline Cellulose (KG-802) 126.00 126.00 outer layer Sodium Octadecyl Fumarate 3.60 3.60 the total 230.0 230.0

Table 9-2. The preparation ratio in the outer layer (wt %)

the the Example 8-1 Example 8-2 outer layer D-mannitol 23.0 23.0 outer layer polyvinylpolypyrrolidone 5.0 5.0 outer layer Microcrystalline Cellulose (KG-802) 70.0 70.0 outer layer Sodium Octadecyl Fumarate 2.0 2.0 the total 100.0 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 9-3 to show the physical properties of the product tablets. In the case where the thickness ratio of the inner core is 32-54%, the tablet achieves an oral disintegration time of 30 seconds or less, an absolute hardness of 2.0 N/mm ² or more, and a high value of HDBI (which is indicator of balance between hardness and disintegratability).

Table 9-3. Tablet Physical Properties

the Example 8-1 Example 8-2 Oral disintegration time (seconds) 20 14 Absolute hardness (N/mm ² ) 3.3 2.2 HDBI 0.17 0.16 Tablet thickness (mm) 3.82 3.79 Core thickness (mm) 1.23 2.03 Thickness ratio of inner core (%) 32 54

Example 9-1: Compression-coated orally disintegrating tablet comprising an active ingredient

(1) Preparation of granules containing acetaminophen (manufactured by Asahi Kasei Chemicals Co., Ltd.)

Acetaminophen was coated to prepare particles containing acetaminophen at a coating rate of 10 wt%. The coating material used herein contained Aquacoat ^™ (manufactured by Asahi Kasei Chemical Co., Ltd.), triacetin and mannitol at 100:25:50 (wt%), respectively. Formulations containing the active ingredient were prepared in the same manner as in Example 1-1 according to the formulation shown in Table 10-1. Final compression into tablets is performed at a pressure of 4 kN.

Table 10-1. Formula (mg)

the the Example 9-1 Inner core Granules containing acetaminophen 28.57 Inner core Polyvinylpolypyrrolidone (Polyplasdone XL-10) 10.71 Inner core talc 10.71 outer layer D-mannitol 131.40 outer layer polyvinylpolypyrrolidone 9.00 outer layer Microcrystalline Cellulose (KG-802) 36.00 outer layer Sodium Octadecyl Fumarate 3.60 the total 230.0

Table 10-2. The preparation ratio in the outer layer (wt %)

the the Example 9-1 outer layer D-mannitol 73.0 outer layer polyvinylpolypyrrolidone 5.0 outer layer Microcrystalline Cellulose (KG-802) 20.0 outer layer Sodium Octadecyl Fumarate 2.0 the total 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 10-3 to show the physical properties of the product tablets. The tablet achieved an oral disintegration time of 30 seconds or less, an absolute hardness of 2.0 N/mm ² or greater, and a high value of HDBI (which is an indicator of a balance of hardness and disintegrability). Therefore, it was concluded that a tablet comprising the active ingredient could also provide a press-coated orally disintegrating tablet with good properties.

Table 10-3. Physical Properties of Tablets

the Example 9-1 Oral disintegration time (seconds) 18 Absolute hardness (N/mm ² ) 3.2 HDBI 0.17

(2) Preparation of particles comprising Gasmotin

To 567 g of purified water was added 31.5 g of polysorbate 80 [Japanese Pharmacopoeia polysorbate 80 (HX): manufactured by NOF Co., Ltd.] and the mixture was well mixed. Then, 73.5 g of talc (produced by Hayashi Kasei Co., Ltd.) and 52.5 g of croscarmellose sodium (Ac-Di-Sol: produced by FMC BioPolymer Co., Ltd.) were added thereto and The mixture was stirred well ("Mixture I"). Separately, a solution of additional sodium hydroxide (2.85 g)/purified water (67.65 g) was slowly added to 705 g of methacrylic acid copolymer LD (POLYQUID PA-30S: produced by Sanyo Chemical Industries Ltd.) and the mixture was stirred. Mixture ("Mixture II"). To mixture I is added mixture II to be suspended. The suspension was sieved through a sieve (177 μm) to obtain a coating dispersion.

346.5 g of Gasmotin and 3.5 g of light anhydrous silicic acid (Aerosil 200: produced by Nippon Aerosil Co., Ltd.) were sieved through a sieve (500 μm) and thoroughly mixed in a polyethylene bag to prepare a drug-containing composition . Then, the composition was put into a Wurster fluidized bed granulator equipped with a forced circulation device (improved Wurster fluidized bed granulator, MP-01 SPC, produced by Powrex Co.), and the coating prepared above was sprayed. layer dispersion. Spraying is carried out at an inlet air temperature of 80°C to 90°C and an outlet air temperature of 26°C to 30°C, and production is carried out while spraying the spray liquid from the bottom spray device under the following conditions: flow rate 10g/min to 12g/min, spray air flow rate 80L/min, injection air pressure 0.2MPa to 0.3MPa, side air pressure 0.20MPa to 0.25MPa, and inlet air flow rate about 0.30m ³ /min to 0.55m ³ /min. Coating was completed when the amount of coating dispersion was about 1306 g, and the resulting particles were dried until the outlet air temperature reached 42°C. The obtained granules were sieved through a 32-mesh (opening: 500 μm) sieve to prepare drug-containing granules having an average particle size of about 165 μm.

Preparations containing granules containing the active ingredient in the inner core were prepared according to the formulation shown in Table 11-1. Granules containing Gasmotin, a mixture of polyvinylpolypyrrolidone and talc were used for the inner core. First, mix the ingredients for the outer layer. A portion (40mg) of the mixture was placed in a mold (diameter 6mm) and the mold was shaken gently to smooth the surface of the powder (which was the lower part of the outer layer). On the mixture, 50 mg of the mixture of inner cores was placed, and then the layered material was temporarily pressed under low pressure (3 kN) using a manual press (oil press system, produced by RIKEN). The temporarily pressed mass was placed concentrically on a punch (8 mm in diameter) in such a way that the lower part of the outer layer lay down. A mold (diameter 8mm) was overlaid and an additional mixture of the above outer layer ingredients (for the sides and upper part of the outer layer, 140 mg) was placed on top of the temporarily compressed mass. The composition between the die and punch was finally compressed under a pressure of 4 kN to produce the desired press-coated orally disintegrating tablet.

Table 11-1. Formulation (mg)

the the Example 9-2 Inner core Granules containing Gasmotin 28.57 Inner core Polyvinylpolypyrrolidone (Polyplasdone XL-10) 10.71 Inner core talc 10.71 outer layer D-mannitol 41.40 outer layer polyvinylpolypyrrolidone 9.00 outer layer Microcrystalline Cellulose (KG-802) 126.00 outer layer Sodium Octadecyl Fumarate 3.60 the total 230.0

Table 11-2. The preparation ratio in the outer layer (wt %)

the the Example 9-2 outer layer D-mannitol 23.0 outer layer polyvinylpolypyrrolidone 5.0 outer layer Microcrystalline Cellulose (KG-802) 70.0 outer layer Sodium Octadecyl Fumarate 2.0 the total 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 11-3 to show the physical properties of the product tablets. The tablet achieved an oral disintegration time of 30 seconds or less, an absolute hardness of 2.0 N/mm ² or greater, and a high value of HDBI (which is an indicator of a balance of hardness and disintegrability). Therefore, it was concluded that a tablet comprising the active ingredient could also provide a press-coated orally disintegrating tablet with good properties.

Table 11-3. Physical Properties of Tablets

the Example 9-2 Oral disintegration time (seconds) 27 Absolute Hardness (N/mm ² ) 4.0 HDBI 0.15

Comparative Examples 5-1 to 5-4: Ordinary tablets (ie, tablets without cores)

A normal tablet (ie, a tablet not including an inner core) was prepared using the outer layer composition shown in Example 1-1. First, the ingredients shown in Table 12-1 were uniformly mixed in the ratios shown in the table. The mixture (230 mg) was compressed into tablets (diameter 8 mm) under a pressure of 4, 10, 15 or 20 kN to prepare each normal tablet.

Table 12-1. Formula (mg)

the Comparative Examples 5-1 to 5-4 D-mannitol 167.9 corn starch 11.5 Microcrystalline Cellulose (KG-802) 46.0 Sodium Octadecyl Fumarate 4.6 total 230.0

Table 12-2. Preparation ratio (wt %)

the Comparative Examples 5-1 to 5-4 D-mannitol 73.0 corn starch 5.0 Microcrystalline Cellulose (KG-802) 20.0 Sodium Octadecyl Fumarate 2.0 total 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. The results are listed in Table 12-3 to show the physical properties of the product tablets.

Tablets have an oral disintegration time of 30 seconds or more when compressed with a force of 15 kN or greater. When the tablet is compressed with a force of 4 kN, it has an absolute hardness of less than 1.0. Regardless of compression pressure, all tablets had HDBI values of 0.15 or less, where HDBI is an indicator of the balance of hardness and disintegrability.

Table 12-3. Physical Properties of Tablets

the Comparative example 5-1 Comparative example 5-2 Comparative example 5-3 Comparative example 5-4 the 4 kN 10 kN 15 kN 20kN Oral disintegration time (seconds) 17 26 39 45 Absolute hardness (N/mm ² ) 0.8 2.8 3.8 4.2 HDBI 0.05 0.11 0.10 0.09

Comparative Example 6-1: Ordinary tablet uniformly containing granules without formability (ie, tablet without core)

The mixture of the ingredients of the inner core and the outer layer shown in Example 1-1 was used to prepare an ordinary tablet in which granules having no formability were uniformly distributed in the tablet. First, the ingredients shown in Table 13-1 were uniformly mixed in the ratios shown in the table. Normal tablets were prepared by compressing the mixture into tablets (8 mm in diameter) under a pressure of 10 kN.

Note that ordinary tablets were prepared under the same conditions as the compression-coated tablets in Example 1-1 (for example, the content of each ingredient/tablet, the weight of the tablet, the diameter of the tablet and the compression force are the same), and The two tablets (ie plain tablet and press-coated tablet) differ only in structure and distribution of non-formable granules.

Table 13-1. Formulation (mg)

the Comparative example 6-1 Microcrystalline Cellulose Balls (CELPHERE CP-203) 50.0 D-mannitol 131.4 corn starch 9.0 Microcrystalline Cellulose (KG-802) 36.0 Sodium Octadecyl Fumarate 3.6 Total (mg) 230.0

Table 13-2. Preparation ratio (wt %)

the Comparative example 6-1 Microcrystalline Cellulose Balls (CELPHERE CP-203) 21.7 D-mannitol 57.1 corn starch 3.9 Microcrystalline Cellulose (KG-802) 15.7 Sodium Octadecyl Fumarate 1.6 total 100.0

The oral disintegration time, hardness, and thickness of the product tablets were measured; the absolute hardness and HDBI were calculated. As shown in Table 13-3, compared with compression-coated tablets, ordinary tablets have low absolute hardness and slow oral disintegration time.

Therefore, for an orally disintegrating tablet containing a large amount of non-formable granules, it is inferred that a press-coated tablet containing granules inside has preferable physical properties compared to an ordinary tablet in which the granules are uniformly distributed.

Table 13-3. Physical Properties of Tablets

the Comparative example 6-1 (common tablet) Example 1-1 (press-coated tablet) Oral disintegration time (seconds) 26 14 Absolute hardness (N/mm ² ) 1.9 2.1 HDBI 0.07 0.15

Industrial Applicability

The present invention can provide a press-coated orally disintegrating tablet whose inner core has poor formability and which has a preferable balance between hardness and disintegrability.

Claims (14)

1. the oral cavity disintegration tablet of the outer pressed coated that surrounds the inner core that contains the powder/bulk material with poor formability, wherein

The thickness of inner core is the 30-80% of the thickness of whole tablet; And

Skin comprises (a) microcrystalline Cellulose, (b) sugar or sugar alcohol, and (c) one or more select free crospovidone, and starch, the special component of the group of the hydroxypropyl cellulose of low replacement and carmellose composition,

Condition is,

In the time that special component (c) comprises starch, the content of starch is 3-40wt%, by outer 100wt%; With

Select free crospovidone when special component (c) comprises one or more, when the composition of the group of the hydroxypropyl cellulose of low replacement and carmellose composition, the content that special component amounts to is 3-20wt%, by outer 100wt%.

2. the oral cavity disintegration tablet of the pressed coated of claim 1, wherein inner core comprises microcapsule class functional particulate.

3. the oral cavity disintegration tablet of the pressed coated of claim 1, wherein inner core, except microcapsule class functional particulate, comprises the powder/bulk material with poor formability.

4. the oral cavity disintegration tablet of the pressed coated of any one in claim 1-3, its ectomesoderm has the porosity of 1-20%.

5. the oral cavity disintegration tablet of the pressed coated of any one in claim 1-3, wherein inner core has the porosity of 10-90%.

6. the oral cavity disintegration tablet of the pressed coated of any one in claim 1-3, wherein the content of microcrystalline Cellulose (a) is 10-90wt%, by outer 100wt%.

7. the oral cavity disintegration tablet of the pressed coated of any one in claim 1-3, wherein the content of microcrystalline Cellulose (a) is 20-70wt%, by outer 100wt%.

8. the oral cavity disintegration tablet of the pressed coated of any one in claim 1-3, wherein

Special component (c) comprises starch; With

The content of starch is 20-40wt%, by outer 100wt%.

9. the oral cavity disintegration tablet of the pressed coated of any one in claim 1-3, wherein

The content of microcrystalline Cellulose (a) is 20-70wt%, by outer 100wt%;

Special component (c) comprises starch; With

The content of starch is 20-40wt%, by outer 100wt%.

10. the oral cavity disintegration tablet of the pressed coated of any one in claim 1-3, wherein starch comprises corn starch.

The oral cavity disintegration tablet of the pressed coated of any one in 11. claim 1-3, wherein sugar or sugar alcohol (b) comprise mannitol.

The oral cavity disintegration tablet of the pressed coated of any one in 12. claim 1-3, the 30-70% of the thickness that wherein thickness of inner core is whole tablet.

The oral cavity disintegration tablet of the pressed coated of any one in 13. claim 1-3, wherein the porosity of inner core is greater than outer field porosity.

The oral cavity disintegration tablet of the pressed coated of any one in 14. claim 1-3, wherein inner core comprises active component.